A novel in vitro metabolomics approach for neurotoxicity testing, proof of principle for methyl mercury chloride and caffeine

There is a need for more efficient methods giving insight into the complex mechanisms of neurotoxicity. Testing strategies including in vitro methods have been proposed to comply with this requirement. With the present study we aimed to develop a novel in vitro approach which mimics in vivo complexity, detects neurotoxicity comprehensively, and provides mechanistic insight. For this purpose we combined rat primary re-aggregating brain cell cultures with a mass spectrometry (MS)-based metabolomics approach. For the proof of principle we treated developing re-aggregating brain cell cultures for 48h with the neurotoxicant methyl mercury chloride (0.1-100muM) and the brain stimulant caffeine (1-100muM) and acquired cellular metabolic profiles. To detect toxicant-induced metabolic alterations the profiles were analysed using commercial software which revealed patterns in the multi-parametric dataset by principal component analyses (PCA), and recognised the most significantly altered metabolites. PCA revealed concentration-dependent cluster formations for methyl mercury chloride (0.1-1muM), and treatment-dependent cluster formations for caffeine (1-100muM) at sub-cytotoxic concentrations. Four relevant metabolites responsible for the concentration-dependent alterations following methyl mercury chloride treatment could be identified using MS-MS fragmentation analysis. These were gamma-aminobutyric acid, choline, glutamine, creatine and spermine. Their respective mass ion intensities demonstrated metabolic alterations in line with the literature and suggest that the metabolites could be biomarkers for mechanisms of neurotoxicity or neuroprotection. In addition, we evaluated whether the approach could identify neurotoxic potential by testing eight compounds which have target organ toxicity in the liver, kidney or brain at sub-cytotoxic concentrations. PCA revealed cluster formations largely dependent on target organ toxicity indicating possible potential for the development of a neurotoxicity prediction model. With such results it could be useful to perform a validation study to determine the reliability, relevance and applicability of this approach to neurotoxicity screening. Thus, for the first time we show the benefits and utility of in vitro metabolomics to comprehensively detect neurotoxicity and to discover new biomarkers.

Association between melanism, physiology and behaviour: a role for the melanocortin system.

The melanocortin system is implicated in the expression of many phenotypic traits. Activation of the melanocortin MC(1) receptor by melanocortin hormones induces the production of brown/black eumelanic pigments, while activation of the four other melanocortin receptors affects other physiological and behavioural functions including stress response, energy homeostasis, anti-inflammatory and sexual activity, aggressiveness and resistance to oxidative stress. We recently proposed the hypothesis that some melanocortin-physiological and -behavioural traits are correlated within individuals. This hypothesis predicts that the degree of eumelanin production may, in some cases, be associated with the regulation of glucocorticoids, immunity, resistance to oxidative stress, energy homeostasis, sexual activity, and aggressiveness. A review of the zoological literature and detailed experimental studies in a free-living population of barn owls (Tyto alba) showed that indeed melanic coloration is often correlated with the predicted physiological and behavioural traits. Support for predictions of the hypothesis that covariations between coloration and other phenotypic traits stem from pleiotropic effects of the melanocortin system raises a number of theoretical and empirical issues from evolutionary and pharmacological point of views.

Auditory-somatosensory multisensory interactions are spatially modulated by stimulated body surface and acoustic spectra

Previous research has provided inconsistent results regarding the spatial modulation of auditory-somatosensory interactions. The present study reports three experiments designed to investigate the nature of these interactions in the space close to the head. Human participants made speeded detection responses to unimodal auditory, somatosensory, or simultaneous auditory-somatosensory stimuli. In Experiment 1, electrocutaneous stimuli were presented to either earlobe, while auditory stimuli were presented from the same versus opposite sides, and from one of two distances (20 vs. 70cm) from the participant's head. The results demonstrated a spatial modulation of auditory-somatosensory interactions when auditory stimuli were presented from close to the head. In Experiment 2, electrocutaneous stimuli were delivered to the hands, which were placed either close to or far from the head, while the auditory stimuli were again presented at one of two distances. The results revealed that the spatial modulation observed in Experiment 1 was specific to the particular body part stimulated (head) rather than to the region of space (i.e. around the head) where the stimuli were presented. The results of Experiment 3 demonstrate that sounds that contain high-frequency components are particularly effective in eliciting this auditory-somatosensory spatial effect. Taken together, these findings help to resolve inconsistencies in the previous literature and suggest that auditory-somatosensory multisensory integration is modulated by the stimulated body surface and acoustic spectra of the stimuli presented.

Development and validation of a clinical prediction rule for chest wall syndrome in primary care.

ABSTRACT: BACKGROUND: Chest wall syndrome (CWS), the main cause of chest pain in primary care practice, is most often an exclusion diagnosis. We developed and evaluated a clinical prediction rule for CWS. METHODS: Data from a multicenter clinical cohort of consecutive primary care patients with chest pain were used (59 general practitioners, 672 patients). A final diagnosis was determined after 12 months of follow-up. We used the literature and bivariate analyses to identify candidate predictors, and multivariate logistic regression was used to develop a clinical prediction rule for CWS. We used data from a German cohort (n = 1212) for external validation. RESULTS: From bivariate analyses, we identified six variables characterizing CWS: thoracic pain (neither retrosternal nor oppressive), stabbing, well localized pain, no history of coronary heart disease, absence of general practitioner's concern, and pain reproducible by palpation. This last variable accounted for 2 points in the clinical prediction rule, the others for 1 point each; the total score ranged from 0 to 7 points. The area under the receiver operating characteristic (ROC) curve was 0.80 (95% confidence interval 0.76-0.83) in the derivation cohort (specificity: 89%; sensitivity: 45%; cut-off set at 6 points). Among all patients presenting CWS (n = 284), 71% (n = 201) had a pain reproducible by palpation and 45% (n = 127) were correctly diagnosed. For a subset (n = 43) of these correctly classified CWS patients, 65 additional investigations (30 electrocardiograms, 16 thoracic radiographies, 10 laboratory tests, eight specialist referrals, one thoracic computed tomography) had been performed to achieve diagnosis. False positives (n = 41) included three patients with stable angina (1.8% of all positives). External validation revealed the ROC curve to be 0.76 (95% confidence interval 0.73-0.79) with a sensitivity of 22% and a specificity of 93%. CONCLUSIONS: This CWS score offers a useful complement to the usual CWS exclusion diagnosing process. Indeed, for the 127 patients presenting CWS and correctly classified by our clinical prediction rule, 65 additional tests and exams could have been avoided. However, the reproduction of chest pain by palpation, the most important characteristic to diagnose CWS, is not pathognomonic.

Therapeutic drug monitoring and pharmacogenetic tests as tools in pharmacovigilance.

Therapeutic drug monitoring (TDM) and pharmacogenetic tests play a major role in minimising adverse drug reactions and enhancing optimal therapeutic response. The response to medication varies greatly between individuals, according to genetic constitution, age, sex, co-morbidities, environmental factors including diet and lifestyle (e.g. smoking and alcohol intake), and drug-related factors such as pharmacokinetic or pharmacodynamic drug-drug interactions. Most adverse drug reactions are type A reactions, i.e. plasma-level dependent, and represent one of the major causes of hospitalisation, in some cases leading to death. However, they may be avoidable to some extent if pharmacokinetic and pharmacogenetic factors are taken into consideration. This article provides a review of the literature and describes how to apply and interpret TDM and certain pharmacogenetic tests and is illustrated by case reports. An algorithm on the use of TDM and pharmacogenetic tests to help characterise adverse drug reactions is also presented. Although, in the scientific community, differences in drug response are increasingly recognised, there is an urgent need to translate this knowledge into clinical recommendations. Databases on drug-drug interactions and the impact of pharmacogenetic polymorphisms and adverse drug reaction information systems will be helpful to guide clinicians in individualised treatment choices.

Oculopalatal tremor: variations on a theme by Guillain and Mollaret.

BACKGROUND: Oculopalatal tremor (OPT) is a delayed complication of a brainstem lesion, characterized by involuntary contractions of the soft palate associated with a synchronized ocular pendular nystagmus. MRI reveals inferior olivary nucleus hypersignal/hypertrophy (IONH). Our objective was to refine the clinical profile of patients with OPT and to report a few oddities in both presentation and evolution. METHODS: We performed a retrospective study of patients diagnosed with OPT and a literature search. RESULTS: From our database, we retrieved 5 men and 3 women with a diagnosis of OPT. Eighty-two patients with OPT were retrieved from the literature and were compiled with our series. The average age was 54 years and there was a male predominance. Brainstem vascular lesion was the most common etiology (80%). Prominent vertical pendular nystagmus was found in 90%. Dissociated nystagmus was mostly associated to unilateral contralateral IONH on MRI, while bilateral symmetrical nystagmus was due to a bilateral IONH in the majority of cases. Three oddities were found amongst our 8 patients: prominent nystagmus ipsilateral to IONH; disappearance of IONH on MRI despite persisting nystagmus, and asymptomatic OPT. CONCLUSION: The clinical profile of OPT is rather stereotyped. Rarely do patients deviate from the classical description of OPT.

Robust parametric indirect estimates of the expected cost of a hospital stay with covariates and censored data.

We consider the problem of estimating the mean hospital cost of stays of a class of patients (e.g., a diagnosis-related group) as a function of patient characteristics. The statistical analysis is complicated by the asymmetry of the cost distribution, the possibility of censoring on the cost variable, and the occurrence of outliers. These problems have often been treated separately in the literature, and a method offering a joint solution to all of them is still missing. Indirect procedures have been proposed, combining an estimate of the duration distribution with an estimate of the conditional cost for a given duration. We propose a parametric version of this approach, allowing for asymmetry and censoring in the cost distribution and providing a mean cost estimator that is robust in the presence of extreme values. In addition, the new method takes covariate information into account.

India in Translation through Hindi Literature. A Plurality of Voices

What role have translations from Hindi literary works played in shaping and transforming our knowledge about India? In this book, renowned scholars, translators and Hindi writers from India, Europe, and the United States offer their approaches to this question. Their articles deal with the political, cultural, and linguistic criteria germane to the selection and translation of Hindi works, the nature of the enduring links between India and Europe, and the reception of translated texts, particularly through the perspective of book history. More personal essays, both on the writing process itself or on the practice of translation, complete the volume and highlight the plurality of voices that are inherent to any translation. As the outcome of an international symposium held at the University of Lausanne, Switzerland, in 2008, India in Translation through Hindi Literature engages in the building of critical histories of the encounter between India and the «West», the use and impact of translations in this context, and Hindi literature and culture in connection to English (post)colonial power, literature and culture.

The Conceptualisation and Measurement of Issue Ownership

Issue ownership means that some parties are considered by the public at large as being more able to deal with, or more attentive to, certain issues. The theory has been used to explain both party behaviour - parties are expected to focus on owned issues - and voter behaviour - when a voter considers a party to own an issue, this affects the odds of voting for that party. The purpose of this article is, first, to provide a look backward at the existing research through a literature review of the studies that were conducted in the past decade-and-a-half. Secondly, it takes stock of the current conceptualisation and argues that issue ownership is a multidimensional concept. Thereafter the article discusses how this multidimensionality affects both the role of issue ownership in voter and in party behaviour. Finally, the article outlines a number of shortcomings of the extant literature and discusses potential avenues for future research.

The Articulation of Different Life Domains among Female Senior Managers and Their Subjective Well-Being : Focusing on Meaning Constructions in Everyday Life

Work-life issues have become a major concern across Western societies with the objective to promote women's careers and well-being. However, despite growing attempts to increase the number of women in senior management positions in European countries, such as Switzerland, they remain highly underrepresented. Inspired from the cultural approach in psychology, this article focuses on these women's concrete everyday life to understand how they articulate different life domains and how this influences their subjective well-being. A narrative approach based on reflexivity is adopted to analyze women's activity. Results show meaning intertwinements between life priorities that are often conflicting. Two psychological functions are identified: the feeling of control and the letting go of control. Each of these contributes to women's subjective well-being through the use of diversified supports, but their structuring roles appear only in relation to one another. Results are discussed in the light of existing literature and of their implications.

The uncertain relationship between transparency and accountability revisited through four Swiss cases

Accountability and transparency are of growing importance in contemporary governance. The academic literature have broadly studied the two concepts separately, defining and redefining them, and including them into various framework, sometimes mistakenly using them as synonyms. The relationship between the two concepts has, curiously, only been studied by a few scholars with preliminary approaches. This theoretical paper will focus on both concepts, trying first to describe them taking into account the various evolutions in the literature and the recent evolutions as well as the first attempts to link the two concepts. In order to show a new approach linking the concepts, four cases from the Swiss context will be portrayed and will demonstrate the necessity to reconsider the relationship between transparency and accountability. Consequently, a new framework, based on Fox's framework (2007) will be presented and theoretically delimited.

Professionalisation of sport federations - a multi-level framework for analysing forms, causes and consequences

Research question: International and national sport federations as well as their member organisations are key actors within the sport system and have a wide range of relationships outside the sport system (e.g. with the state, sponsors, and the media). They are currently facing major challenges such as growing competition in top-level sports, democratisation of sports with 'sports for all' and sports as the answer to social problems. In this context, professionalising sport organisations seems to be an appropriate strategy to face these challenges and current problems. We define the professionalisation of sport organisations as an organisational process of transformation leading towards organisational rationalisation, efficiency and business-like management. This has led to a profound organisational change, particularly within sport federations, characterised by the strengthening of institutional management (managerialism) and the implementation of efficiency-based management instruments and paid staff. Research methods: The goal of this article is to review the current international literature and establish a global understanding of and theoretical framework for analysing why and how sport organisations professionalise and what consequences this may have. Results and findings: Our multi-level approach based on the social theory of action integrates the current concepts for analysing professionalisation in sport federations. We specify the framework for the following research perspectives: (1) forms, (2) causes and (3) consequences, and discuss the reciprocal relations between sport federations and their member organisations in this context. Implications: Finally, we work out a research agenda and derive general methodological consequences for the investigation of professionalisation processes in sport organisations.

Literature report : a review of policy learning in five strands of political science research

This paper reviews the policy learning literature in political science. In recent years, the number of publications on learning in the political realm increased dramatically. Researchers have focused on how policymakers and administrators adapt policies based on learning processes or experiences. Thereby, learning has been discussed in very different ways. Authors have referred to learning in the context of ideas, understood as deeply held beliefs, and, as change and adaptation of policy instruments. Two other strands of literature have taken into consideration learning, namely the diffusion literature and research on transfer, which put forward learning to understand who learns from whom and what. Opposed to these views, political learning emphasizes the adaptation of new strategies by policymakers over the transfer of knowledge or broad ideas. In this approach, learning occurs due to the failure of existing policies, increasing problem pressure, scientific innovations, or a combination of these elements.

Le sentiment de gratitude en soins palliatifs : un facteur contribuant au bien-être et à la qualité de vie ? [Gratitude in palliative care: is it a psychological factor contributing to well-being and quality of life?]

En s'appuyant sur la littérature scientifique et l'état de la recherche, cet article a pour objectif de montrer pourquoi la prise en compte du sentiment de gratitude peut s'avérer utile dans le contexte palliatif en mettant en évidence dans quelle mesure cette émotion ou disposition individuelle: 1) entre en résonance avec le concept de croissance posttraumatique et certains enjeux relationnels chez les patients en fin de vie; 2) représente un facteur favorisant le bien-être et la qualité de vie; 3) peut être considérée comme un facteur protecteur contre les troubles psychopathologiques. Based on the scientific literature and the state of research, this article aims to show why the feeling of gratitude may represent a point of interest for palliative care. We will highlight the following in this article: 1) why this feeling of gratitude resonates with the concept of post-traumatic growth and relational challenges in end-of-life patients; 2) in which measure this feeling represents a factor contributing to well-being and quality of life; 3) in which measure this feeling may be considered as a protective factor against psychopathological troubles.